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Notch1 And T-All (T-cell Acute Lymphoblastic Leukemia) Katie Lozada. How Notch was discovered. -Discovered in Drosophila 1917 by Thomas Hunt Morgan -Notch pathway is highly conserved between Drosophila and humans. Notch1 is a cell surface receptor. -plays a key role in cell fate decisions.

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Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch1

And

T-All

(T-cell Acute Lymphoblastic Leukemia)

Katie Lozada


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

How Notch was discovered

-Discovered in Drosophila 1917 by Thomas Hunt Morgan

-Notch pathway is highly conserved between Drosophila and humans


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch1 is a cell surface receptor

-plays a key role in cell fate decisions


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Overview of the Notch Pathway

Ligand binds to Notch extracellular domain

 induces proteolytic cleavage

 releases intracellular domain

 enters nucleus, activate CSL

 alter gene expression!


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Overview of Notch Pathway

Maillard et al. Fig 1.


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch Signaling can have diverse effects

Stem Cells

Bipotent Thymocytes

Tcell

Bcell

Inhibit Differentiation

Promote Tcell fate

Radtke et al. Fig 2.


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch Signaling can have diverse effects

Skin Cells

Tcells

Terminal differentiation

ONCOGENE

Radtke et al. Fig 2.


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch1 knockout mice die at E 9.5 with defects in forming somites

This precluded analysis of its role in the lymphocyte lineage


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Specifically knock out Notch 1 in adult mice somites

After its roles in embryonic development are over


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Interferon somites

Promoter

Korf et al. Fig. 4-17.




Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch plays multiple roles in T cells thymus

Commitment to T-cell Lineage:

-inactivated Notch1  no T cells, accumulate B

-constitutively active Notch1  no B cells, accumulate T


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch plays multiple roles in T cells thymus

Grabher et al. Fig 3.


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Oncogenic Activity of Notch thymus

Maillard et al. Fig. 1


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Oncogenic Activity of Notch1 thymus

Oncogenic signal  differentiation block

inhibition of cell cycle arrest and apoptosis


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

T-ALL is a cancer of Lymphoblasts thymus

-Uncontrolled T-cell Proliferation

-TCR breakpoints in 30%-35% of T-ALL cases


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Translocation causes constitutively active Notch1 thymus

Translocation between Notch1 gene and TCRβ locus

Constitutively active


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Notch Tumorigenesis thymus

-maintains precursor cells in proliferating and undifferentiated state


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

T-cell Acute Lymphoblastic Leukemia thymus

Notch activation leads to activation of as yet unknown genes involved in T cell fate

It’s constitutive activation leads to

 T cell proliferation and malignancy


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

T-cell Acute Lymphoblastic Leukemia thymus

-T-ALL accounts for 10-15% of diagnosed Acute Lymphoblastic Leukemias

-Mainly diagnosed in children (age 2-5)

-Affects boys more than girls

-Associated with large thymus


Notch1 and t all t cell acute lymphoblastic leukemia katie lozada

Treatment for T-ALL thymus

-Systemic disease requires multi-drug chemotherapy

-High survival rate among treated patients